From the Department of Anaesthesiology and Intensive Care, Croix-Rousse Hospital (CHU), Hospices Civils de Lyon (HCL), HESPER 7425, Claude Bernard Lyon 1 University, Lyon (FA); Sorbonne Université (OL, LB, FK, J-SH, BR), UMRS INSERM 1166, IHU ICAN, Paris, France; Assistance Publique-Hôpitaux de Paris (APHP), Department of Anaesthesiology and Critical Care (OL, NB), Department of Pharmacology (NZ, J-SH), Department of Biostatistics (NC, LB), Department of Orthopaedic Surgery (FK) and Department of Emergency Medicine and Surgery (BR), Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Eur J Anaesthesiol. 2018 Jul;35(7):496-504. doi: 10.1097/EJA.0000000000000793.
Among the various factors that may influence the pharmacological response to opioids, genetic polymorphisms [single nucleotide polymorphisms (SNP)] have generated some interest.
To examine the influence on morphine dose requirements and adverse events in the postoperative period of four SNP [opioid receptor mu1 (OPRM1), ATP-binding cassette subfamily B, member 1 (ABCB1) ex-21 and ex-26, catechol-o-methyltransferase (COMT)] in candidate genes involved in morphine pharmacodynamics and pharmacokinetics.
A single centre prospective study.
University Hospital, Paris, France, from 2 January 2007 to 15 November 2011.
A total of 438 white adults scheduled for major orthopaedic surgery (spine, hip and knee) under general anaesthesia. The main exclusion criteria were receiving opioids for chronic pain, nonopioid drugs within 2 days prior to surgery, pregnancy, renal insufficiency, sleep apnoea obstruction syndrome, morbid obesity, severe hepatic impairment, cognitive dysfunction.
Assays of plasma concentrations of morphine and metabolites (morphine 3-glucuronide and morphine 6-glucuronide) were performed and common polymorphisms in four candidate genes [OPRM1 A118G rs1799971; P-glycoprotein (ABCB1) T3435C (rs1045642) and G2677T/A (rs2032582); COMT Val 158 Met (rs4680)] were analysed.Morphine was titrated by staff in the postanaesthesia care unit (PACU) and in the ward patient-controlled intravenous analgesia was used for 24 h.
The dose of morphine required to achieve pain relief and the influence of SNP in genes involved in morphine pharmacodynamics and kinetics on morphine dose requirements. Secondary endpoints were the concentrations of morphine, morphine 6-glucuronide and morphine 3-gluguronide, the proportion of patients requiring a rescue analgesic and the proportion of morphine-related adverse events.
A total of 404 patients completed the study to final analysis. The mean ± SD morphine dose to achieve pain relief was 15.8 ± 8.8 mg in the PACU and 22.7 ± 18.6 mg during patient-controlled intravenous administration. Morphine-related adverse events were observed in 37%. There was no relationship between any genetic polymorphisms and morphine dose, morphine 3-gluguronide and morphine 6-glucuronide concentration, morphine-related adverse events or pain level. In the PACU only, P-glycoprotein polymorphisms (ex-21; ex-26) were significantly associated with morphine concentration but the prediction of the model was poor (R = 0.04) CONCLUSION: No major relationship has been demonstrated between SNP of OPRM1, ABCB1, COMT and morphine requirement, pain level or adverse effects in the postoperative period.
NCT00822549 (www.clinicaltrials.gov).
在可能影响阿片类药物药理反应的各种因素中，遗传多态性[单核苷酸多态性（SNP）]引起了一些关注。
研究候选基因中与吗啡药效动力学和药代动力学相关的四个 SNP[阿片受体 mu1（OPRM1）、ATP 结合盒亚家族 B，成员 1（ABCB1）外显子 21 和外显子 26、儿茶酚-O-甲基转移酶（COMT）]对吗啡剂量需求和术后不良事件的影响。
单中心前瞻性研究。
法国巴黎大学医院，2007 年 1 月 2 日至 2011 年 11 月 15 日。
共 438 名白人成年患者，拟在全身麻醉下接受主要矫形手术（脊柱、髋关节和膝关节）。主要排除标准为：慢性疼痛接受阿片类药物治疗、术前 2 天内使用非阿片类药物、怀孕、肾功能不全、睡眠呼吸暂停阻塞综合征、病态肥胖、严重肝损伤、认知功能障碍。
检测血浆中吗啡及其代谢物（吗啡 3-葡糖苷酸和吗啡 6-葡糖苷酸）的浓度，并分析四个候选基因中的常见 SNP[阿片受体 mu1（OPRM1）A118G rs1799971；P 糖蛋白（ABCB1）T3435C（rs1045642）和 G2677T/A（rs2032582）；COMT Val 158 Met（rs4680）]。吗啡由 PACU 中的工作人员滴定，病房患者自控静脉镇痛 24 小时。
达到疼痛缓解所需的吗啡剂量以及吗啡药效动力学和动力学相关基因中的 SNP 对吗啡剂量需求的影响。次要终点是吗啡、吗啡 6-葡糖苷酸和吗啡 3-葡糖苷酸的浓度、需要解救镇痛的患者比例以及与吗啡相关的不良事件的比例。
共有 404 名患者完成了研究的最终分析。PACU 中达到疼痛缓解所需的吗啡平均剂量为 15.8 ± 8.8mg，患者自控静脉给药时为 22.7 ± 18.6mg。37%的患者出现与吗啡相关的不良事件。任何遗传多态性与吗啡剂量、吗啡 3-葡糖苷酸和吗啡 6-葡糖苷酸浓度、吗啡相关不良事件或疼痛水平之间均无相关性。仅在 PACU 中，P 糖蛋白多态性（外显子 21；外显子 26）与吗啡浓度显著相关，但模型预测效果不佳（R=0.04）。
在术后期间，OPRM1、ABCB1、COMT 的 SNP 与吗啡需求、疼痛水平或不良事件之间未显示出主要关系。
NCT00822549（www.clinicaltrials.gov）。
